CN102918118A - Fluorescent dye material and use thereof - Google Patents

Fluorescent dye material and use thereof Download PDF

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CN102918118A
CN102918118A CN2011800271332A CN201180027133A CN102918118A CN 102918118 A CN102918118 A CN 102918118A CN 2011800271332 A CN2011800271332 A CN 2011800271332A CN 201180027133 A CN201180027133 A CN 201180027133A CN 102918118 A CN102918118 A CN 102918118A
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chemical formula
compound
complex compound
salen complex
metal
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石川义弘
江口晴树
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IHI Corp
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    • A61K49/00—Preparations for testing in vivo
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
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    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

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Abstract

The usefulness of an iron-salen complex can be extended. Thus, disclosed is a novel fluorescent dye material comprising a compound represented by chemical formula (I). In the formula, M represents Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd. N,N'-Bis(salicylidene)ethylenediamine metal.

Description

Fluorochrome material and using method thereof
Technical field
The present invention relates to contain fluorescence formula material and the using method thereof of metal salen complex compound.
Background technology
Usually, medicine arrives affected part after being administered to organism, produces result for the treatment of by bringing into play pharmacological effect in this affected part part, even but medicine arrives affected part tissue (being healthy tissues) in addition, can not treat.
Therefore, it is very important how effectively medicine to be guided to affected part.The technology that medicine is guided to affected part is called as drug delivery (drug delivery), is the active field of carrying out of research in recent years exploitation.This drug delivery has at least two advantages.
An advantage is to obtain fully high drug level in affected tissue.Do not produce pharmacological effect if the drug level in the affected part reaches more than the certain value, can't expect result for the treatment of during lower concentration.
Second advantage is medicine only can be guided to affected tissue, suppresses the side effect of normal tissue.
Such drug delivery is brought into play effect most for the cancer therapy of using carcinostatic agent to carry out.Therefore carcinostatic agent also can suppress the active tissue of cell fission, such as the cell proliferation of marrow or root of hair, gastrointestinal mucosal etc. because major part is to suppress the material of the cell proliferation of the active cancer cells of cell fission in healthy tissues.
Therefore, the cancer patients who has accepted the carcinostatic agent administration can produce the side effects such as anaemia, alopecia, vomiting.Because these side effects become white elephant for the patient, therefore must limit dosage, thereby have the problem that can't fully obtain the pharmacological effect of carcinostatic agent.
In these anti-malignant-tumor agents, alkylating agent is that anti-malignant-tumor agent is to have the alkyl of making (CH 2-CH 2-) be combined in the general name of the carcinostatic agent of the ability on nucleic acid-protein etc.By making the DNA alkylation hinder dna replication dna, thereby cause necrocytosis.
This effect and cell cycle irrespectively work, to G 0The effect of the cell that the cell of phase and propagation are active is all strong, thereby easily marrow, gastrointestinal mucosal, sexual cell, root of hair etc. is caused damage.
In addition, antimetabolic is that anti-malignant-tumor agent is the compound that has with the metabolite similar structures of nucleic acid, albumen building-up process, damages cell by hindering synthetic grade of nucleic acid, thereby the cell of division stage is played specific effect.
In addition, the antitumor activity microbiotic is the chemical substance by microorganisms, has the effects such as the DNA of inhibition is synthetic, cut-out DNA chain, thereby shows anti-tumor activity.
In addition, microtubule inhibitors is by forming spindle body when cell fission, or directly acts on the microtubule that plays a significant role of keeping of the cell normal functions such as configuration to [Dan in the cell, material conveying, thereby shows antitumous effect.Microtubule inhibitors works to the active cell of cell fission, neurocyte etc.
In addition, synthetic thereby the platinum preparation passes through to form DNA chain or interchain bond or DNA protein binding obstruction DNA.Cis-platinum is representative drugs, but strong to renal impairment, needs a large amount of fluid infusion.
In addition, the similar medicine of hormone is that anti-malignant-tumor agent is effective for the dependent tumour of hormone.For the dependent prostate cancer of male hormones, the anti-male hormones agent of administration estrogen or administration.
In addition, molecular targeted medicine is corresponding to the molecule of the specific molecular biological property therapeutics as target in various malignant tumours.
In addition, topoisomerase enzyme inhibitor is by introduce the enzyme that otch changes the chain number of rings of DNA chain at DNA temporarily.Topoisomerase I is to introduce otch at a chain of cyclic DNA, another chain is passed through after, close the enzyme of otch; Topoisomerase enzyme inhibitor II is 2 chains that temporarily cut off cyclic DNA, and 2 other chain DNAs are passed through, and reconnects the enzyme of otch again.
In addition, nonspecific immunity strengthening agent comes the propagation of anticancer by activated immune system.
Because most of carcinostatic agents suppress the cell proliferation of the active cancer cells of cell fission, therefore in healthy tissues, also suppress the active tissue of cell fission, such as the cell proliferation of marrow or root of hair, gastrointestinal mucosal etc.Therefore, in the cancer patients who has accepted the carcinostatic agent administration, can produce the side effects such as anaemia, alopecia, vomiting.
Because these side effects become white elephant for the patient, therefore must limit dosage, thereby have the problem that can't fully obtain the pharmacological effect of carcinostatic agent.In addition, the worst situation may be owing to side effect causes death.
Therefore, expectation arrives cancer cells by drug delivery guiding carcinostatic agent, and concentrates on cancer cells, makes its performance pharmacological effect, can effectively carry out cancer therapy when suppressing side effect thus.Same problem also is present in local anesthetic.
The itching of the parts such as the mucous membrane that local anesthetic causes for the treatment of hemorrhoid, oral inflammation, periodontopathy, carious tooth, exodontia or operation etc., skin, pain.As representative local anesthetic, known have a benefit cacaine (trade(brand)name: bitter breath happy cacaine), although lignocaine quick-acting is excellent, but has the arrhythmia effect.
In addition, when carrying out Spinal Anesthesia, if injection then can be spread in spinal fluid as the lignocaine of narcotic in spinal fluid, be owing to the spinal cord that arrives neck causes respiratory function to stop to cause serious side effects thereby the someone worries the worst situation.
Therefore, expectation arrives cancer cells by drug delivery guiding carcinostatic agent, and concentrates on cancer cells, makes its performance pharmacological effect, can effectively carry out cancer therapy when suppressing side effect thus.
In addition, expectation prevents the diffusion of local anesthetic by drug delivery, and realizes that drug effect continues and the alleviating of side effect.
As the concrete grammar of drug delivery, the method for use carrier (carrier) is for example arranged.The method be with drug loading on the carrier that concentrates on easily affected part, and medicine is transported to affected part.
As carrier, being considered most promising is magnetic substance, has proposed to make carrier as magnetic substance to be attached on the medicine and is gathered in the method (for example, with reference to patent documentation 1) of affected part by magnetic field.
Yet, when the magnetic substance carrier is used as carrier, known: the oral administration difficulty, carrier molecule is usually large especially, and there are technical problem in the bonding strength between carrier and drug molecule, affinity aspect, thereby eventually are difficult to practical.
Therefore, the inventor proposes: to the basic framework of the organic compound side chain in conjunction with the spin electric density that is used for giving plus or minus, with respect to the external magnetic field, integral body has the adaptability of the scope that magnetic induces jointly, when being applicable to human body, animal, thereby provide in the scope in magnetic field by coming exogenic magnetic field to remain on the part, in aforementioned range, to bring into play the remedy,topical of the effect of drugs of originally possessing.In this communique, put down in writing iron salen complex compound as such medicine.(with reference to patent documentation 2).
In addition, the antitumor drug that contains iron salen complex compound is also disclosed.(for example, with reference to patent documentation 3).
The prior art document
Patent documentation
Patent documentation 1: TOHKEMY 2001-10978 communique
Patent documentation 2:WO2008/001851 communique
Patent documentation 3: TOHKEMY 2009-173631 communique
Summary of the invention
The problem that invention will solve
The object of the invention is to enlarge the availability of iron salen complex compound.
Solve the method for problem
In order to realize this purpose, the present invention is for containing the new fluorochrome material of following chemical formula (I).(N, the inferior quadrol metal of N '-two (salicylidene))
（N,N’-Bis(salicylidene)ethylenediamine?metal）
Chemical formula (I)
Figure BDA00002503002800041
Wherein, M is Fe(iron), Cr(chromium), Mn(manganese), the Co(cobalt), Ni(nickel), the Mo(molybdenum), the Ru(rubidium), the Rh(rhodium), the Pd(palladium), W(tungsten), the Re(rhenium), the Os(osmium), Ir(iridium), Pt(platinum), the Nd(neodymium), the Sm(samarium), the Eu(europium) or the Gd(gadolinium).
Particularly M is the phosphorescence that the compound of iron sends the wavelength of 300nm to 500nm.Therefore, as putting down in writing in the TOHKEMY 2009-173631 communique with the metal salen complex compound of chemical combination formula (I) as antitumor drug, be administered to the individualities such as human body, animal, and after magnetic guides to the target cancerous tissue, when the resection operation of affected tissue, to affected tissue irradiating laser, fluorescence, thereby make metal salen complex compound luminous, can confirm affected tissue by vision.
For the median size of described metal salen complex compound, when particle diameter was excessive, compound might artery-clogging.On the other hand, particle diameter hour might lose the magnetic of compound.Therefore, the median size of compound is suitably for 2～60 μ m, is preferably 5～20 μ m, and more preferably 8～15 μ m are particularly preferably 9～12 μ m, and the best is 10 μ m.
Particle diameter is adjusted in this scope and can implements in recrystallizing technology.For example, " the compound recrystallization in the solution of diethyl ether and paraffin that makes gained " in synthesis step 7 described later, arranged, temporarily make temperature rise to 80 ℃ before the recrystallization, then be cooled to room temperature through 12 hours, thereby can obtain target grain size.
The result that the inventor studies, the magnetization characteristic of described metal salen complex compound changes according to particle diameter.Particle diameter is little when surpassing necessary degree, metal salen complex compound magnetization characteristic is insufficient, be administered to human body, animal etc. when individual, might can't guide to the target area by the external magnetic field, on the other hand, particle diameter increases to when surpassing necessary degree, might magnetic particle cohesion in blood vessel.
As described in TOHKEMY 2009-173631 communique, the represented iron salen complex compound conduct of chemical formula (I) has after being administered to individuality in the situation of not utilizing magnetic carrier, individuality (is for example used the external magnetic field, 0.3T) time, it is useful that described molecule is directed to the antitumor drug of magnetic in the zone that has applied described magnetic field.
The invention effect
As mentioned above, according to the present invention, can obtain the new fluorescent material of described chemical formula (I).
Description of drawings
Fig. 1 is the luminous test result's of expression metal salen complex compound performance chart.
Fig. 2 is the particle size determination result's of expression metal salen complex compound performance chart.
Embodiment
The manufacturing of metal salen complex compound (iron salen)
Step 1:
Figure BDA00002503002800051
25g, 0.18mol as compound 1(compound1) 4-nitrophenols (4-nitrophenol) in add to mix vulkacit H (hexamethylenetetramine), the 200ml polyphosphoric acid (polyphosphoric acid) of 25g, 0.18mol, this mixture was stirred 1 hour at 100 ℃.Afterwards this mixture is dropped in the water of the ethyl acetate of 500ml and 1L, stir until fully dissolving.Add the ethyl acetate of 400ml in this solution for continuous, this solution separating is 2 phases as a result again.Then, remove water from these mutually, remaining compound with basic solvent washing 2 times, and is used anhydrous MgSO 4Make its drying, the result has synthesized 17g(yield 57%) compound 2(compound 2).
Step 2:
Figure BDA00002503002800061
Compound 2(compound 2 at 17g, 0.10mol) adds 200ml diacetyl oxide (aceticanhydride), a small amount of sulfuric acid (H in 2SO 4), at room temperature stirred 1 hour.Then, the solution of gained was mixed 0.5 hour in the 2L frozen water, be hydrolyzed.The solution of gained is passed through strainer, and carry out drying in atmosphere, the result obtains the material of white powder.The solution that use contains ethyl acetate makes this powder recrystallization, and the result can obtain 24g(yield 76%) compound 3(compound 3) white crystal.
Step 3:
Figure BDA00002503002800062
Compound 3(compound 3 at 24g, 77mmol) the carbon 2.4g of 10% palladium that mixed 500ml methyl alcohol and load in reduces this mixture one night in the hydrogen reduction atmosphere of 1.5 air pressure.After the end, use strainer to filter, the result has synthesized the compound 4(compound 4 of dark brown oily) 21g.
Step 4,5:
Figure BDA00002503002800071
The compound 4(compound4 that in 200ml anhydrous methylene chloride (DCM), adds 21g, 75mmol) and the di-tert-butyl dicarbonic acid ester (di (tert-butyl) dicarbonate) of 18g, 82mmol, one night of stirring in nitrogen atmosphere.Afterwards, make the solution (compound 5(compound 5) of gained) in a vacuum the evaporation after, dissolve with 100ml methyl alcohol.Afterwards, add sodium hydroxide and the 50ml water of 15g, 374mmol, refluxed 5 hours.Afterwards cooling, after the strainer filtration, washing with water, dry in a vacuum, the result obtains dark brown compound.The compound of gained carries out the flash chromatography that uses silica gel 2 times, thereby obtains 10g(yield 58%) compound 6(compound 6).
Step 6:
The compound 6(compound 6 that in dehydrated alcohol 400ml, adds 10g, 42mmol), refluxes while heat, in dehydrated alcohol 20ml, add the several quadrols of 1.3g, 21mmol and stirred 0.5 hour.Then, the container of this mixing solutions being put into ice cools off and stirred 15 minutes.Afterwards, with the washing with alcohol of 200ml and by strainer, carry out drying under vacuum, the result has synthesized 8.5g(yield 82%) compound 7(compound 7).
Step 7:
The compound 7(compound 7 that in the 50ml anhydrous methanol, adds 8.2g, 16mmol) and the triethylamine (triethylamine) of 22ml, 160mmol, will in 10ml methyl alcohol, add the iron(ic) chloride (FeCl of 2.7g, 16mmol 3) solution of gained under nitrogen atmosphere, mixed at room temperature 1 hour, the result obtains dark brown compound.Then carry out in a vacuum drying.
With methylene dichloride 400ml the compound of gained is diluted, with basic solution washing 2 times, with sodium sulfate (Na 2SO 4) carry out drying after, carry out in a vacuum drying, make compound recrystallization in the solution of diethyl ether and paraffin of gained, and measure by high performance liquid chromatography, the result obtains 5.7g(yield 62%) the complex compound A(complex A of purity more than 95%: iron salen complex compound).
Use in the situation of iron salen complex compound metal complex in addition, as long as utilize the muriate (MCl of the metal beyond the iron 3: wherein, M is metal) replace iron(ic) chloride (FeCl 3) get final product.In addition, has the magnetic of the degree that can guide by the external magnetic field in the manganese salen complex compound beyond the iron salen complex compound, chromium salen complex compound, the cobalt salen complex compound as shown in the application applicant's Japanese patent application 2009-177112 communique.And it is also clear and definite in TOHKEMY 2009-173631 communique that metallic iron salen complex compound etc. has antitumor action.
＜luminous test＞
For the represented iron salen complex compound of chemical formula (I), utilize photoluminescence determination to carry out luminous test.
Mensuration is made made high de-agglomeration spectrum analysis by the hole field and is carried out with PHOTOLUMINOR-S.Be determined at and iron salen be dissolved under the state in the chloroform carry out.
The Fig. 1 that the results are shown in gained.According to Fig. 1, can confirm near 380nm, to produce the intrinsic peak of the represented iron salen complex compound of chemical formula (I).In addition, among Fig. 1, although near 270nm, 530nm, 800nm, confirm the peak, its for be excited laser (vibrate simultaneously send the laser of white light with several wavelength of RGB) with reference to the peak.Spike length changes according to the crystalline state of iron salen complex compound.
＜particle size determination＞
Measure the particle diameter of the iron salen complex compound of chemical formula (I) with laser diffractometry.Measuring employed device is Microtrac particle-size analyzer (MT-3000II processed of Nikkiso Company Limited).Sample is dropped in the hexa metaphosphoric acid Na solution, disperse the sample irradiating laser line of 10 minutes gained to using homogenizer, measure its diffraction (scattering), obtain granularity.Condition determination and measurement result are as follows.
＜condition determination＞
Minute: 30 seconds
Particle perviousness: see through
Particle shape: non-sphere
Particle specific refractory power: 1.81
Solvent: water
Solvent specific refractory power: 1.333
＜measurement result＞
The results are shown in Fig. 2 and following with what measure.
Median size: 11.79 μ m
Standard deviation: 6.289
The result who measures as can be known, the particle diameter of iron salen complex compound is for extremely being suitable for 11.8 individual μ m.
As mentioned above, metal salen complex compound above-mentioned iron salen complex compound etc., that can fluorescence add lustre to is administered to individuality, individuality is used magnetic field and after metal salen complex compound guided to the target area, when using exterior light, can confirm the luminous of metal salen complex compound from the outside.
Claims (according to the modification of the 19th of treaty)
1.(after revising) a kind of fluorochrome material, it contains metal salen complex compound, and the peak position of emission wavelength is in visibility region.
2.(append) fluorochrome material according to claim 1, described metal salen complex compound is made of following chemical formula (I).
Chemical formula (I)
Figure FDA00002503003500011
N, the inferior quadrol metal of N '-two (salicylidene)
Wherein, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.
3.(after revising) fluorochrome material according to claim 1, the M of described chemical formula (I) is Fe, has the peak of emission wavelength near 380nm.
4.(after revising) each described fluorochrome material in 3 according to claim 1, after the metal salen complex compound of described chemical formula (I) is administered to individuality, by being directed to the target area and bringing into play pharmacological effect from individual external magnetic field.
5.(after revising) fluorochrome material according to claim 4, the M of described chemical formula (I) is Fe, metal salen complex compound has after being administered to individuality in the situation of not utilizing magnetic carrier, when individuality is used the external magnetic field, be directed to the magnetic in the zone that has applied described magnetic field.
6.(after revising) each described fluorochrome material in 5 according to claim 1, the particle diameter of the compound of described chemical formula (I) is 2～60 μ m.
7.(after revising) a kind of using method of fluorochrome material, the fluorochrome material that will contain the metal salen complex compound that is made of following chemical formula (I) is administered to individuality, and use magnetic field from the outside to this individuality, thereby after this material guided to the target area, use exterior light, make the described fluorochrome material that is positioned at described target area luminous.
Chemical formula (I)
Figure FDA00002503003500021
N, the inferior quadrol metal of N '-two (salicylidene)
Wherein, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

Claims (6)

1. fluorochrome material, it contains the metal salen complex compound that is made of following chemical formula (I),
Chemical formula (I)
Figure FDA00002503002700011
N, the inferior quadrol metal of N '-two (salicylidene)
Wherein, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.
2. fluorochrome material according to claim 1, the M of described chemical formula (I) is Fe, sends the phosphorescence of the wavelength of 300nm～500nm.
3. fluorochrome material according to claim 1 and 2 is after the metal salen complex compound of described chemical formula (I) is administered to individuality, by being directed to the target area and bringing into play pharmacological effect from individual external magnetic field.
4. fluorochrome material according to claim 3, the M of described chemical formula (I) is Fe, metal salen complex compound has after being administered to individuality in the situation of not utilizing magnetic carrier, when individuality is used the external magnetic field, is directed to the magnetic in the zone that has applied described magnetic field.
5. each described fluorochrome material in 4 according to claim 1, the particle diameter of the compound of described chemical formula (I) is 2～60 μ m.
6. the using method of a fluorochrome material, the fluorochrome material that will contain the metal salen complex compound that is made of following chemical formula (I) is administered to individuality, and use magnetic field from the outside to this individuality, thereby after this material guided to the target area, use exterior light, make the described fluorochrome material that is positioned at described target area luminous.
Chemical formula (I)
Figure FDA00002503002700021
N, the inferior quadrol metal of N '-two (salicylidene)
Wherein, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.
CN2011800271332A 2010-06-01 2011-05-12 Fluorescent dye material and use thereof Pending CN102918118A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2010-126021 2010-06-01
JP2010126021 2010-06-01
PCT/JP2011/002651 WO2011151978A1 (en) 2010-06-01 2011-05-12 Fluorescent dye material and use thereof

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Publication Number Publication Date
CN102918118A true CN102918118A (en) 2013-02-06

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